Water-insoluble ruthenium catalyst composition for use in aqueous hydrogenation reactions

ABSTRACT

The invention relates to a method for converting a precatalyst complex to an active catalyst complex, wherein the precatalyst complex and the active catalyst complex comprise a ruthenium atom and an optically active ligand that is insoluble in water, and the active catalyst complex furthermore comprises a monohydride and a water molecule. The method comprises the steps of providing water as an activation solvent system with a pH value equal or below 2, and solving said precatalyst complex, an acid, and hydrogen therein. The invention further relates to a method for manufacturing a catalyst composition, a method for hydrogenating a substrate molecule and a reaction mixture.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is the U.S. National Stage of International Application No.PCT/EP2014/054291, filed Mar. 5, 2014, which was published in Englishunder PCT Article 21(2), which in turn claims the benefit of EP PatentApplication No. 13157998.9, filed Mar. 6, 2013.

The present invention relates to a method for converting an inactiveruthenium precatalyst into an active catalyst in aqueous solutions. Thepresent invention further relates to a method for manufacturing awater-insoluble chiral catalyst, and to its use.

Pure enantiomers are used in the synthesis of, inter alia,pharmaceuticals, agrochemicals, flavours and fragrances. Asymmetricchemocatalysis is an efficient production method for chiral molecules.Current large-scale protocols, however, rely on the use of organicsolvents, making these methods expensive and problematic from a safetyand environmental impact point of view.

Chiral noble-metal complexes in aqueous solutions are known in the art.Kan-To Wan et al. (Tetrahedron Asymmetry, Pergamon Press Ltd, Oxford,GB, pages 2461-2467, 1 Jan. 1993) shows a sulfonated ruthenium BINAP(Binaphtalendiyl-bis[diphenylphosphine) complex. WO2007104690 shows aruthenium phosphine complex. U.S. Pat. No. 5,827,794 shows a sulfonatedruthenium BINAP complex.

Asymmetric synthesis employing metal catalysts with chiral ligands aredescribed in U.S. Pat. No. 5,324,870, which shows the use of a chiralruthenium phosphine complex in hydrogenation reactions, in Touati et al.(Tetrahedron Asymmetry, Pergamon Press Ltd, Oxford, GB, pages 3400-3405,27 Dec. 2006), which shows asymmetric hydrogenation reactions catalysedby a ruthenium SYNPHOS complex, in Duprat et al. (Tetrahedron Letters,44(4), pages 823-826, 2003), which shows a ruthenium SYNPHOS complex,and in WO9215400 which shows a ruthenium BINAP complex.

In summary, known methods for asymmetric catalysis use organic solvents.Water is a desirable solvent for conducting asymmetric syntheses withruthenium catalysts, particularly in view of technical-scaleapplications.

Rhodium-catalyzed asymmetric hydrogenations of different substrates inaqueous/surfactant media and/or biphasic systems have been explored byGrassert et al. (J. Organomet. Chem., 621, pages 158-165, 2001) theyshow a 1,5-cyclooctadiene)bismethylallylrhodium phosphine complex.

The ligands used in aqueous solutions differ from conventional chiralligands—which are insoluble in water—by the addition of chemical groupsto render them water soluble. This modification is expensive.

The ability to use water-insoluble chiral ligands in aqueous phasecatalysis would be of advantage. To the knowledge of the presentinventors, however, chiral synthesis employing chiral water-insolubleruthenium containing catalysts in aqueous media has not beenaccomplished so far.

Based on this background, it is the objective of the present inventionto provide means and methods for chiral hydrogenation reactions inaqueous media.

Surprisingly it was found that under conditions of low pH,water-insoluble catalysts can be made and used in aqueous media,particularly in the absence of any organic solvent. It was further foundthat such catalyst can be activated in aqueous media.

The present invention provides a method for converting a precatalystcomplex to an active catalyst complex, wherein the precatalyst complexcomprises a ruthenium atom and an optically active ligand, and whereinthe active catalyst complex comprises the ruthenium atom, the opticallyactive ligand, a monohydride and at least one water molecule, andwherein the monohydride and the water molecule are bound to saidruthenium atom, and wherein the optically active ligand is insoluble inwater. The nature of the bond between the ruthenium atom and the watermolecule or the monohydride is covalent or coordinative in nature. Themethod of the invention comprises the steps of providing water as anactivation solvent system, and solving the precatalyst complex an acid,and hydrogen in the activation solvent system at a pH value of theactivation solvent system equal or below 2.

According to a first aspect of the invention, a method for converting aprecatalyst complex to an active catalyst complex is provided,

-   -   wherein the precatalyst complex and the active catalyst complex        comprise a ruthenium atom and an optically active ligand that is        insoluble in water, and    -   wherein the active catalyst complex furthermore comprises a        monohydride and a water molecule,    -   the method comprising the steps of:    -   a) providing water as an activation solvent system,    -   b) adding to, particularly solving in, said activation solvent        system:        -   the precatalyst complex,        -   a solubilizer,        -   an acid, and        -   hydrogen,    -   characterized in that the final pH value of the activation        solvent system is equal or below 2 after addition of the acid.

The monohydride and the water molecule are bound to the ruthenium atom.

A precatalyst complex in the context of the present specification refersparticularly to a complex comprising an optically active ligand that(the ligand) is insoluble in water, a ruthenium atom, and optionally asolvent molecule selected from an organic polar solvent and water,whereby the solvent molecule is bound to the ruthenium atom.

Such precatalyst complex is not able to hydrogenate a double bondselected from C═O and C═N in a substrate molecule; particularly thedouble bond cannot be hydrogenated in absence of a monohydride bound tothe ruthenium atom; likewise, in a precatalyst, the solvent moleculebound to the ruthenium atom is not substitutable against a substratemolecule in an aqueous solvent system.

An active catalyst complex in the context of the present specificationrefers particularly to a compound comprising an optically active ligandthat (again, the ligand) is insoluble in water, a ruthenium atom, atleast one water molecule and a monohydride being bound to the rutheniumatom. Such active catalyst complex is configured to reduce a double bondselected from C═O and C═N in a substrate molecule, the monohydrideserving as the reducing agent. Without wishing to be bound by theory, itappears that the solvent molecule can be substituted by the substratemolecule mentioned above in an aqueous solvent system, and one half ofthe substrate molecule's double bond is hydrogenated by the monohydride,while the other half of the double bond may be hydrogenated byelementary hydrogen solved in the solvent system, wherein thehydrogenation is performed. The inventors hypothesize, again withoutwishing to be bound by theory, that the underlying mechanism involvesblocking of the catalytic complex by water molecules at neutral pH.

An optically active ligand in the context of the present specificationrefers to a compound that is capable of binding to the ruthenium atomdescribed above and is characterized by an optical activity, whereinoptical activity or optical rotation is the turning of the plane oflinearly polarized light as the light travels through the ligand.Accordingly, there are at least two enantiomeric forms of the opticallyactive ligand, wherein each form rotates the plane of light in anopposite direction.

The term “insoluble in water” in the context of the presentspecification particularly refers to a solubility of an entity of below0.02 mol/l, 0.01 mol/l, 0.005 mol/l or 0.001 mol/l at 25° C.

A monohydride in the context of the present specification refers to ahydrogen atom with one electron, whereby this electron participates inthe bonding between the hydrogen atom and the ruthenium atom, while theother electron of the bond is provided by the ruthenium atom.

A solubilizer in the context of the present specification refers to acompound or composition, the presence of which increases the solubilityin water of poorly soluble or non-soluble compounds or compositions. Insome embodiments, the solubilizer is a non-ionic surfactant or anorganic solvent that is miscible with water.

In some embodiments, the activation solvent system comprises at least(≧)25% (v/v), ≧50% (v/v), ≧75% (v/v), ≧80% (v/v), ≧90% (v/v), ≧99% (v/v)or 100% (v/v) water.

In some embodiments, the precatalyst complex comprises a monohydridebound to the ruthenium complex. Such precatalyst complex with boundmonohydride can be converted to an active catalyst complex by the methodfor converting a precatalyst complex to an active catalyst complexaccording to the invention, with the exception that the method may beperformed without solving hydrogen in the activation solvent system.

In some embodiments, the acid is characterized by a pKa value of <0.

In some embodiments, the acid is a hydrogen acid. In some embodiments,the acid is characterized by formula HX, wherein X is the correspondinganionic base.

In some embodiments, the acid deprotonates after solving in theactivation solvent system, whereby the resulting corresponding anionicbase of the acid binds to the ruthenium atom. The nature of the bondbetween the ruthenium atom and the corresponding anionic base iscovalent or coordinative in nature.

In some embodiments, the acid is selected from the group comprised ofsulphuric acid, nitric acid, sulfonic acid, perchloric acid, perbromicacid, fluorosulfuric acid, hydrobromic acid, hydrochloric acid,hydriodic acid and fluoroboric acid.

In some embodiments, an acid solution is solved in the activationsolvent system, wherein the acid solution is characterized by an acidconcentration of 0.05 N, 0.1 N, 0.2 N, 0.3 N, 0.4 N, 0.5 N, 0.6 N, 0.7N, 0.8 N, 0.9 N, 1 N, 1.5 N, 2 N, 2.5 N or 3 N.

In some embodiments, the optically active ligand is a bidentate ligandor a monodentate ligand.

In some embodiments, one bidentate ligand is bound to the rutheniumatom. In some embodiments, two monodentate ligands are bound to theruthenium atom. The nature of the bond between the ruthenium atom andthe monodentate ligand or the bidentate ligand is covalent orcoordinative in nature.

In some embodiments, the catalyst complex is characterized by two watermolecules bound to the ruthenium atom.

In some embodiments, the precatalyst complex is characterized by formulaI

wherein

-   -   L₁ and L₂ are independently from another a monodentate optically        active ligand, or L₁ and L₂ together form a bidentate optically        active ligand,    -   S is an organic solvent molecule comprising 1, 2, 3, 4, 5, 6, 7        or 8 carbon atoms and optionally at least one oxygen atom, or a        water molecule,    -   R¹ is F, Cl, Br, I, BF₄, SO₃F, ClO₄, SO₄, NO₃, actetate or        cymene.    -   R² is a hydrogen (monohydride) or R¹.

In some embodiments, the organic solvent molecule is selected frommethanol, trichloromethane, dichloromethane, ethanol, trifluoroethanol,n-propanol, 2-propanol, n-butanol, 2-butanol, n-pentanol, 2-pentanol,3-pentanol, n-hexanol, 2-hexanol, 3-hexanol, hexane, heptane and octane.

In some embodiments, the active catalyst complex is characterized byformula II

wherein L₁, L₂ have the same meaning as described above, and X is R¹described above or the corresponding anionic base to the acid HXdescribed above.

In some embodiments, the water molecule bound to the ruthenium leavesthe catalyst as oxonium (H₃O⁺), when being substituted against thesubstrate molecule.

Such active catalyst complex is suitable to perform a catalytic cycle,wherein at least one water molecule bound to the ruthenium atom aresubstituted by a substrate molecule comprising a double bond selectedfrom C═O and C═N, one partner of the double bond is hydrogenated by themonohydride bound to the ruthenium atom, the other partner ishydrogenated by a monohydride from elementary hydrogen, the hydrogenatedsubstrate molecule is cleaved off the ruthenium atom and a monohydridebinds to the ruthenium atom thereby regenerating the active catalystcomplex.

In some embodiments, the optically active ligand is selected from thegroup comprised of:

-   -   Synphos (5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxane)

-   -   Segphos (5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole):

-   -   BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)

-   -   DIOP        (O-isopropyliden-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane):

-   -   DIPAMP (ethane-1,2-diylbis[(2-methoxyphenyl)phenylphosphane]):

-   -   CHIRAPHOS (bis(diphenylphosphino)butane):

-   -   NORPHOS        ((3-diphenylphosphanyl-2-bicyclo[2.2.1]hept-5-enyl)-diphenyl-phosphane):

-   -   DEGUPHOS        ((1-benzyl-4-diphenylphosphanyl-pyrrolidin-3-yl)-diphenyl-phosphane):

-   -   PROPHOS        ((2-diphenylphosphanyl-1-methyl-ethyl)-diphenyl-phosphane):

-   -   DIMPC        ([2-(diphenylphosphanylmethyl)cyclohexyl]methyl-diphenyl-phosphane):

-   -   BPPM (tert-butyl        4-benzhydryl-2-(2,2-diphenylethyl)pyrrolidine-1-carboxylate):

-   -   BNPE        ([2-(1-naphthyl)phenyl]-[2-[2-(1-naphthyl)phenyl]phosphanylethyl]phosphane):

-   -   MeO-BIHEP        ([2-(2-diphenylphosphanyl-6-methoxy-phenyl)-3-methoxy-phenyl]-diphenyl-phosphane):

-   -   Cl-MeO BIHEP        ([4-chloro-2-(3-chloro-6-diphenylphosphanyl-2-methoxy-phenyl)-3-methoxy-phenyl]-diphenyl-phosphane):

-   -   Cl-MeO-BIHEP        ([5-chloro-2-(4-chloro-2-diphenylphosphanyl-6-methoxy-phenyl)-3-methoxy-phenyl]-diphenyl-phosphane):

-   -   HEXAPHEMP        ([2-(6-diphenylphosphanyl-2,3,4-trimethyl-phenyl)-3,4,5-trimethyl-phenyl]-diphenyl-phosphane:

-   -   P-PHOS        ([3-(4-diphenylphosphanyl-2,6-dimethoxy-3-pyridyl)-2,6-dimethoxy-4-pyridyl]-diphenyl-phosphane):

-   -   TMBTP        ([4-(4-diphenylphosphanyl-2,5-dimethyl-3-thienyl)-2,5-dimethyl-3-thienyl]-diphenyl-phosphane):

-   -   SOLPHOS        ([8-(7-diphenylphosphanyl-4-methyl-2,3-dihydro-1,4-benzoxazin-8-yl)-4-methyl-2,3-dihydro-1,4-benzoxazin-7-yl]-diphenyl-phosphane):

-   -   a compound characterized by formula Ill:

-   -   wherein n is 1, 2, 3, 4, 5 or 6.

In some embodiments, the solubilizer is a polar organic solvent or asurfactant that is capable of forming micelles in water and is resistantto hydrolysis at pH≦2.

In some embodiments, the solubilizer is a non-ionic surfactant,particularly an alkylglycoside, more particularly D-GlycopyranosideC9-C11 alkyl (CAS No. 132778-08-6, obtained from Cognis/BASF AG).

A surfactant in the context of the present specification refers to anamphiphilic compound that lowers the surface tension of a liquid,particularly of water.

A micelle in the context of the present specification refers to asupramolecular spherical aggregate of surfactant molecules dispersed ina liquid, particularly in water. Such aggregate exhibits a hydrophilicsurface that is in contact to the liquid and formed by hydrophilic headsof the surfactant molecules and a lipophilic or hydrophobic core that isshielded from the liquid and formed by the lipophilic tail group of thesurfactant molecules.

In some embodiments, the surfactant is a detergent or tenside comprisinga hydrophilic head group and a lipophilic tail group.

In some embodiments, the hydrophilic head group is an anionic group,wherein the anionic group does not comprise a double bound.

In some embodiments the hydrophilic head is a non-ionic group selectedfrom the group comprised of fatty alcohols, polyoxyethylene glycol alkylethers, polyoxypropylene glycol alkyl ethers and glucosides.

In some embodiments, the hydrophilic head is a cationic group selectfrom tetraalkylammonium and quaternary ammonium cations.

In some embodiments, the lipophilic tails group consists ofhydrocarbons.

In some embodiments, the lipophilic head is selected from aC₃-C₃₀-alkyl, -aryl, -heterocyclyl, -heteroaryl and -carbocyclyl.

The term alkyl or alkyl group in the context of the presentspecification signifies a saturated hydrocarbon moiety, which may belinear, branched, cyclic or cyclic with linear or branched side chains.The term alkyl includes partially unsaturated hydrocarbons such aspropenyl. Examples are n- or isobutyl, n- or cyclohexyl, heptyl, octyl,dodecyl and octadecyl. The term alkyl may extend to alkyl groups linkedor bridged by hetero atoms such as N, S or O.

The term aryl in the context of the present specification signifies acyclic aromatic hydrocarbon. Heteroaryl in the context of the presentinvention are aryls that comprise nitrogen, oxygen or sulfur atoms.Examples of heteroarly are pyrrol, 1,2- or 1,3-diazole, thiadiazole(e.g. 1,2,5-, 1,2,3-), furane, thiophene, indole and its O- andS-homologues, indolizine or pyridine.

The term heterocyclyl in the context of the present specificationsignifies chains or rings, or combinations thereof, of carbon, oxygen,nitrogen and/or sulphur atoms that are connected by single or doublebonds. Examples for heterocyclyl moieties are a morpholino moiety and apiperidinyl moiety.

The term carbocyclyl in the context of the present specificationsignifies rings of carbon or a combination of chains and rings of carbonthat are connected by single bonds. Examples for carbocyclyls arecyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane.

In some embodiments, the surfactant has a decomposition rate constant atpH 2 of not higher than 10 s⁻¹, 1 s⁻¹, 0.1 s⁻¹, 0.01 s⁻¹ or 0.001 s⁻¹ at25° C.

In some embodiments, the surfactant is non-ionic. A non-ionic surfactantin the context of the present specification refers particularly to asurfactant without dissociative groups, particularly without a carboxygroup.

In some embodiments, the surfactant is an alkylglycoside. Analkylglycoside in the context of the present specification refers to acompound comprising a C₁-C₂₀ alkyl alcohol moiety as lipophilic tailgroup and a sugar moiety as hydrophilic head group, wherein the anomerichydroxyl group of the sugar and the hydroxyl group of the alcohol forman actetal bond.

In some embodiments, the surfactant is the alkylglycosideD-Glycopyranoside C9-C11 alkyl (CAS No. 132778-08-6).

In some embodiments, the lipophilic tail group is a C₈-C₁₄ alkyl alcoholmoiety.

In some embodiments, the sugar moiety comprises a monosaccharide or anoligosaccharide.

In some embodiments, the monosaccharide is selected from glucose,fructose, mannose, ribose, galactose and ribulose.

In some embodiments, the oligosaccharide is selected from sucrose,maltose, cellobiose or raffinose.

In some embodiments, the surfactant has a critical micellarconcentration (CMC) value of ≦10 mM, more preferably ≦1 mM, mostpreferably ≦0.25 mM, wherein CMC specifies the lowest concentration ofthe surfactant in water at which spherical micelles are formed at 25° C.and 1 bar.

In some embodiments, the surfactant is provided in the activationsolvent system in a concentration equal or above the surfactant'scritical micelle concentration.

According to a second aspect of the invention, a method for obtaining acatalyst composition is provided, comprising the steps of:

-   a) providing water as a preparation solvent system, and-   b) adding to, particularly solving in, the preparation solvent    system:    -   a first catalyst composition comprising an optically inactive        ligand and a ruthenium atom,    -   an optically active ligand, wherein the optically active ligand        is insoluble in water,    -   a solubilizer, and    -   an acid,        there by the optically inactive ligand in the first catalyst        composition is substituted by the optically active ligand        yielding a second catalyst composition comprising the ruthenium        atom and the optically active ligand, characterized in that the        final pH value of the preparation solvent system is equal or        below 2 after addition of the acid.

A catalyst composition in the context of the present specificationrefers particularly to a compound or composition that can lower theactivation energy of a chemical reaction and accelerate the reaction byat least 3 orders of magnitude, particularly a hydrogenation reaction inpresence of elementary hydrogen. An optically inactive ligand in thecontext of the present specification refers to a compound that iscapable of binding to the metal atom described above and that has nooptical activity.

In some embodiments, the optically inactive ligand is selected from thegroup comprised of 1,5-cyclooctadiene, acetyl acetonate,(1,5-cyclooctadien)bismethylallyl, bis(ethylcyclopentadienyl),bis(pentamethylcyclopentadienyl), p-cymene, diacetato, norbonadiene,cyclohexadiene, cylcoheptandiene, para-methadiene, α-Phellandiene andbenzol.

The terms optically active ligand, acid, solubilizer, surfactant andmicelle have the same meaning as described above.

In some embodiments, the solubilizer is a polar organic solvent misciblein water over a range of 1 part solvent:99 parts water to 1 partsolvent:5 parts water.

In some embodiments, the solubilizer is a preparation surfactant that iscapable of forming micelles in water and resistant to hydrolysis at pH2.

In some embodiments, the preparation solvent system comprises not morethan 50% (v/v), 25% (v/v), 20% (v/v), 10% (v/v) or 1% (v/v) polarorganic solvent.

In some embodiments, the preparation solvent system comprises at least(≧)25% (v/v), ≧50% (v/v), ≧75% (v/v) ≧80% (v/v), ≧90% (v/v), ≧99% (v/v)or 100% (v/v) water.

In some embodiments, the second catalyst composition further comprises awater molecule bound to the ruthenium atom. The nature of the bondbetween the ruthenium atom and the water molecule is covalent orcoordinative in nature.

In some embodiments, the second catalyst composition comprises two watermolecules bound to the ruthenium atom.

In some embodiments, the second catalyst composition is further reactedwith elementary hydrogen, yielding a catalyst composition with amonohydride bound to the ruthenium atom.

The nature of the bond between the ruthenium atom and the monohydride iscovalent or coordinative in nature.

Suchsecond catalyst composition is suitable to perform a catalytic cycleas described above.

In some embodiments, the preparation surfactant is provided in thepreparation solvent system in a concentration equal or above thesurfactant's critical micelle concentration.

In some embodiments, the second catalyst composition is insoluble inwater.

In some embodiments, the preparation solvent system further comprises apH-control agent.

A pH-control agent in the context of the present specification refers toa compound by which the pH of an aqueous solution can be altered. SuchpH-control agent may be an acid, a base or ion exchange resin. A pHcontrol agent may also be a buffer system comprising a combination ofacids and bases that are selected such that the pH value of acomposition comprising the buffer changes less upon addition of an acidor a base than in a corresponding composition without the buffer system.

In some embodiments, the preparation surfactant has a critical micellarconcentration (CMC) value of ≦10 mM, more preferably ≦1 mM, mostpreferably ≦0.25 mM, wherein CMC specifies the lowest concentration ofthe surfactant in water at which spherical micelles are formed at 25° C.and 1 bar.

In some embodiments, the preparation surfactant is non-ionic.

In some embodiments, the preparation surfactant is an alkylglycoside.The term alkylglycoside has the same meaning as described above.

In some embodiments, the preparation surfactant is D-GlycopyranosideC9-C11 alkyl (CAS No. 132778-08-6, obtained from Cognis/BASF AG).

In some embodiments, the acid is characterized by a pKa value of <0.

In some embodiments, the acid is a hydrogen acid.

In some embodiments, the acid is characterized by formula HX, wherein Xis the corresponding anionic base.

In some embodiments, the acid deprotonates after solving in thepreparation solvent system, whereby the resulting corresponding anionicbase of the acid binds to the ruthenium atom comprised within the secondcatalyst composition. The nature of the bond between the ruthenium atomand the corresponding anionic base is covalent or coordinative innature.

In some embodiments, the acid is selected from the group comprised ofsulphuric acid, nitric acid, sulfonic acid, perchloric acid, perbromicacid, fluorosulfuric acid, hydrobromic acid, hydrochloric acid,hydriodic acid, and fluoroboric acid.

In some embodiments, an acid solution is solved in the preparationsolvent system, wherein the acid solution is characterized by aconcentration of 0.1 N, 0.2 N, 0.3 N, 0.4 N, 0.5 N, 0.6 N, 0.7 N, 0.8 N,0.9 N, 1 N, 1.5 N, 2 N, 2.5 N or 3 N.

According to third aspect of the invention, a method for hydrogenating adouble bond in a substrate molecule is provided, the double bond beingselected from the group comprised of C═O and C═N, wherein the methodcomprises the steps of:

-   a) providing a reaction solvent system comprising at least 25% (v/v)    water, and-   b) solving in the reaction solvent system a solubilizer, the    substrate molecule and a catalyst composition comprising a ruthenium    atom and an optically active ligand, wherein the optically active    ligand is insoluble in water,    characterized in that the hydrogenating is performed at pH 2.

Hydrogenating a double bond in context of the present specificationrefers to a chemical reaction, wherein the double bond is converted to asingle bond and hydrogen is added to both partners of the former doublebond.

In some embodiments, the substrate has a molecular mass of more (>) than28, 34, 60 or 72 g/mol. In some embodiments, the substrate molecule isorganic molecule comprising at least 5 atoms of a molecular mass of 12or higher, and comprising a carbonyl (keto, aldehyde) or imine group.

The terms catalytic composition, solubilizer and optically active ligandhave the same meaning as described above.

In some embodiments, the hydrogenation is performed at pH≦2 by furthersolving an acid in the reaction solvent system. The term acid has thesame meaning as described above.

In some embodiments, the reaction solvent system comprises at least 50%(v/v), 75% (v/v) 80% (v/v), 90% (v/v), 99% (v/v) or 100% (v/v) water.

In some embodiments, the acid is a hydrogen acid.

In some embodiments, the acid is characterized by a pKa value of <0.

In some embodiments, the acid is selected from the group comprised ofsulphuric acid, nitric acid, sulfonic acid, perchloric acid, perbromicacid, fluorosulfuric acid, hydrobromic acid, hydrochloric acid,hydriodic acid and fluoroboric acid.

In some embodiments, the solubilizer is a polar organic solvent or areaction surfactant that is capable of forming a micelle in water andresistant to hydrolysis at pH 2. The term surfactant has the samemeaning as described above.

In some embodiments, the reaction solvent system comprises not more than50% (v/v), 25% (v/v), 20% (v/v), 10% (v/v) or 1% (v/v) polar organicsolvent.

In some embodiments, the reaction surfactant is provided in the reactionsolvent system in a concentration equal or above the surfactant'scritical micelle concentration.

In some embodiments, the reaction surfactant has a critical micellarconcentration (CMC) value of not larger than 10 mM, more preferably 1mM, most preferably 0.25 mM, wherein CMC specifies the lowestconcentration of the surfactant in water at which spherical micelles areformed at 25° C. and 1 bar.

In some embodiments, the reaction surfactant is non-ionic.

In some embodiments, the reaction surfactant is an alkylglycoside. Theterm alkylglycoside has the same meaning as described above.

In one embodiment, the reaction surfactant is D-Glycopyranoside C9-C11alkyl (CAS No. 132778-08-6, obtained from Cognis/BASF AG).

In some embodiments, the reaction surfactant is identical to thepreparation surfactant described above.

In some embodiments, the substrate molecule comprises at least 3 carbonatoms.

In some embodiments, the substrate molecule is soluble in the aqueousphase of the reaction solvent system.

In some embodiments, the substrate molecule is an aliphatic or cyclic,saturated or unsaturated compound having a carbonyl or imine group suchketones, aldehydes, aldimines, ketimines, cabon acid or esters.

In some embodiments, the reaction solvent system further comprises apH-control agent. The term pH-control agent has the same meaning asdescribed above.

In some embodiments, the hydrogenation is performed at temperaturesbetween 20° C. and 200° C., preferably between 80° C. and 180° C., morepreferably between 100° C. and 140° C., most preferable between 110° C.and 130° C.

In some embodiments, the reaction solvent system does not compriseorganic solvents.

In some embodiments, the hydrogenating is an asymmetric hydrogenatingreaction. Asymmetric hydrogenating in the context of the presentspecification shall mean that adding hydrogen to the double bond of asubstrate molecule generates a new chiral centre, and that theasymmetric adding results in an addition product in enantiomeric excess(ee) of 50%, 90% or 95%. Enantiomeric excess is defined as the absolutedifference between the mole fraction of each enantiomer. For example anenantiomeric excess of 90% means an addition product with 95 n/n % ofone enantiomer and 5 n/n % of the opposite enantiomer.

In some embodiments, the catalyst composition is obtained by a methodaccording to the second aspect or comprises an active catalyst complexobtained by a method according to the first aspect of the invention.

In some embodiments, the method for hydrogenating a double bond furthercomprises solving an acid in the reaction solvent system.

In some embodiments, the acid is a hydrogen acid.

In some embodiments, the acid is selected from the group comprised ofsulphuric acid, nitric acid, sulfonic acid, perchloric acid, perbromicacid, fluorosulfuric acid, hydrobromic acid, hydrochloric acid,hydriodic acid and fluoroboric acid.

In some embodiments, an acid solution is solved in the reaction solventsystem, wherein the acid solution is characterized by a concentration of0.1 N, 0.2 N, 0.3 N, 0.4 N, 0.5 N, 0.6 N, 0.7 N, 0.8 N, 0.9 N, 1 N, 1.5N, 2 N, 2.5 N or 3 N.

In some embodiments, the substrate molecule is selected from the groupcomprised of:

-   -   hydroxyacetone (1-hydroxypropan-2-one):

-   -   2,4 pentadione:

In some embodiments, the product of the hydrogenating is selected fromthe group comprised of:

-   -   (2R)-propane-1,2-diol:

-   -   (2S)-propane-1,2-diol:

-   -   (2R,4R)-pentane-2,4-diol:

-   -   (2S,4S)-pentane-2,4-diol:

According to fourth aspect of the invention, a reaction mixture isprovided, comprising

-   -   a solvent system comprising at least 25% water,    -   a solubilizer,    -   an active catalyst complex as specified in the first aspect of        the invention or a catalyst composition as specified in the        second aspect of the invention, and    -   a substrate molecule comprising a double bond selected from C═O        and C═N.

The terms solubilizer, surfactant, reaction surfactant, catalystcomplex, catalyst composition and substrate molecule have the samemeaning as described above.

In some embodiments, the solvent system comprises at least 50%, at least75% or at least 95% water or at least 100% water.

In some embodiments, the solubilizer is a polar organic solvent or areaction surfactant as specified in the above embodiments.

In some embodiments, the solvent system comprises not more than 50%(v/v), 25% (v/v), 20% (v/v), 10% (v/v) or 1% (v/v) polar organicsolvent. In some embodiments, the reaction mixture does not compriseorganic solvents.

In some embodiments, the substrate molecule is any of

-   -   hydroxyacetone (1-hydroxypropan-2-one):

-   -   2,4 pentadione:

Wherever reference is made herein to an embodiment of the invention, andsuch embodiment only refers to one feature of the invention, it isintended that such embodiment may be combined with any other embodimentreferring to a different feature. For example, every embodiment thatdefines an optically active ligand may be combined with every embodimentthat defines S, R¹, R² or X to characterize a group of precatalyst oractive catalyst complexes or compositions of the invention or a singlecomplex or composition of the invention with different properties.

The invention is further characterized, without limitations, by thefollowing examples, from which further features, advantages orembodiments can be derived. The examples do not limit but illustrate theinvention.

EXAMPLES Preparation Method I

6.0144*10⁻⁵ mol of (1,5-cyclooctadiene)bismethylallylruthenium and 1.1equivalents of the chiral ligand (such as e.g. SYNPHOS or SEGPHOS) weredissolved in 5 ml ethanol under nitrogen atmosphere. 2.2 equivalents ofa 0.18 N solution of hydrobromic acid in methanol was added and stirredfor 30 minutes at room temperature. Thus, the final concentration ofhydrobromic acid was 0.0001323 mol in 5 ml ethanol, which equates to apH value of 1.57.

Preparation Method II. Catalyst Preparation with Pure Hydrobromic Acid

6.0144*10⁻⁵ mol of (1,5-cyclooctadiene)bismethylallylruthenium and 1.1equivalents of the chiral ligand were dissolved in 5 ml ethanol undernitrogen atmosphere. 2.2 equivalents of 0.18 N hydrobromic acid solutionwas added and stirred for 50 minutes at room temperature. Thus, thefinal concentration of hydrobromic acid was 0.0001323 mol in 5 mlethanol, which equates to a pH value of 1.57.

Preparation Method III. Catalyst Preparation without Organic Solvents

100 mg of alkylpolyglucoside were dissolved in 5 ml of degassed water.27.5 μl of a 45 wt. % hydrobromic acid solution were added. 6.0144*10⁻⁵mol of (1,5-cyclooctadiene)bismethylallylruthenium and 1.1 equivalentsof the chiral ligand were dissolved in the aqueous surfactant solutionand stirred for 30-50 minutes at room temperature. Thus, the finalconcentration of hydrobromic acid was 0.000153 mol in 5 ml water, whichequates to a pH value of 1.5.

Working Example 1

The catalyst solution obtained according to Preparation III, but with(S)-SYNPHOS as chiral ligand was placed into an autoclave in thepresence of 50 ml of ethanol, 275 μl of a 45 wt. % hydrobromic acidsolution as well as 5.4*10⁻³ mol of hydroxyacetone under a hydrogenatmosphere of 1.1 bar pressure. Thus, the final concentration ofhydrobromic acid was 0.0456 mol/l, which equates to a pH value of 1.34.The reaction mixture was stirred and heated at 60° C. for 1 hour. Theenantiomeric excess was then determined by chiral GC (FS LIPODEX Acolumn). As a result, the yield was 100% and the purity of the (S)-formof 1,2-propanediol was more than 97% ee.

Working Example 2

The catalyst solution obtained according to Preparation III, but with(S)-SYNPHOS as chiral ligand was placed into an autoclave in thepresence of 50 ml of degassed water, 275 μl of a 45 wt. % hydrobromicacid solution, 1 g alkylpolyglucoside as well as 5.4*10⁻³ mol ofhydroxyacetone under a hydrogen atmosphere of 4.2 bar pressure. Thus,the final concentration of hydrobromic acid was 0.0456 mol/l, whichequates to a pH value of 1.34. The reaction mixture was stirred andheated at 125° C. for 6 hours. The solution was extracted with ethylacetate. The extract was dried on anhydrous magnesium sulfate. Theenantiomeric excess was then determined by chiral GC (FS LIPODEX A). Asa result, the yield was 100% and the purity of the (S)-form of1,2-propanediol was more than 97% ee.

Working Example 3

The catalyst solution obtained according to Preparation II, but with(S)-SEGPHOS as chiral ligand was placed into an autoclave in thepresence of 50 ml of degassed water, 275 μl of a 45 wt. % hydrobromicacid solution, 1 g alkylpolyglucoside as well as 5.4*10⁻³ mol ofhydroxyacetone under a hydrogen atmosphere of 4.2 bar pressure. Thus,the final concentration of hydrobromic acid was 0.044 mol/l, whichequates to a pH value of 1.36 The reaction mixture was stirred andheated at 125° C. for 3 hours. The solution was extracted with ethylacetate. The extract was dried on anhydrous magnesium sulfate. Theenantiomeric excess was then determined by chiral GC as in Example 1. Asa result, the conversion was 55% and the purity of the (S)-form of1,2-propanediol was more than 97% ee, by a yield of 100% (i.e. 100% ofthe 55% of the starting materials which were converted belong to thedesired product species, which means that no side reactions occurred;the product showed an enantiomeric excess of 97% ee).

Working Example 4

The catalyst solution obtained according to Preparation II, but with(R)-SYNPHOS as chiral ligand is placed into an autoclave in the presenceof, 30 ml of heptane, 20 ml of degassed water, 110 μl of a 45 wt. %hydrobromic acid solution, 1 g alkylpolyglucoside as well as 5.4*10⁻³mol of hydroxyacetone under a hydrogen atmosphere of 4.7 bar pressure.Thus, the final concentration of hydrobromic acid was 0.019 mol/l, whichequates to a pH value of 1.72. The reaction mixture was stirred andheated at 125° C. for 3 hours. The solution was extracted with ethylacetate. The extract was dried on anhydrous magnesium sulfate. Theenantiomeric excess was then determined by chiral GC as in Example 1. Asa result, the yield was 90% and the purity of the (R)-form of1,2-propanediol was more than 97% ee.

Working Example 5

The catalyst solution obtained according to Preparation II, but with(S)-SYNPHOS as chiral ligand is placed into an autoclave in the presenceof, 25 ml of ethanol, 30 ml of degassed water, 165 μl of a 45 wt. %hydrobromic acid solution, 2 ml alkylpolyglucoside as well as 0.51 g ofhydroxyacetone under a hydrogen atmosphere of 1.1 bar pressure. Thus,the final concentration of hydrobromic acid was 0.025 mol/l, whichequates to a pH value of 1.6. The reaction mixture was stirred andheated at 60° C. for 6 hours. The solution was extracted with ethylacetate. The extract was dried on anhydrous magnesium sulfate. Theenantiomeric excess was then determined by chiral GC as in Example 1. Asa result, the yield was 100% and the purity of the (S)-form of1,2-propanediol was more than 97% ee.

Working Example 6

The catalyst solution obtained according to Preparation I, but with(S)-SEGPHOS as chiral ligand was placed into an autoclave in thepresence of, 25 ml of ethanol, 30 ml of degassed water, 165 μl of a 45wt. % hydrobromic acid solution, 2 ml alkylpolyglucoside as well as 0.51g of hydroxyacetone under a hydrogen atmosphere of 1.1 bar pressure.Thus, the final concentration of hydrobromic acid was 0.025 mol/l, whichequates to a pH value of 1.6. The reaction mixture was stirred andheated at 60° C. for 3 hours. The solution was extracted with ethylacetate. The extract was dried on anhydrous magnesium sulfate. Theenantiomeric excess was then determined by chiral GC as in Example 1. Asa result, the yield was 100% and the purity of the (S)-form of1,2-propanediol was more than 97% ee.

Working Example 7

The catalyst solution obtained according to Preparation III, but with(S)-SYNPHOS as chiral ligand was placed into an autoclave in thepresence of, 25 ml of ethanol, 30 ml of degassed water, 165 μl of a 45wt. % hydrobromic acid solution, 2 ml alkylpolyglucoside as well as 0.51g of hydroxyacetone under a hydrogen atmosphere of 1.1 bar pressure.Thus, the final concentration of hydrobromic acid was 0.0266 mol/l,which equates to a pH value of 1.57. The reaction mixture was stirredand heated at 60° C. for 3 hours. The solution was extracted with ethylacetate. The extract was dried on anhydrous magnesium sulfate. Theenantiomeric excess was then determined by chiral GC as in Example 1. Asa result, the conversion was 100% and the purity of the (S)-form of1,2-propanediol was more than 97% ee.

Working Example 9

The catalyst solution obtained according to Preparation I, but with(S)-SYNPHOS as chiral ligand was placed into an autoclave in thepresence of, 25 ml of ethanol, 30 ml of degassed water, 165 μl of a 45wt. % hydrobromic acid solution, 2 ml alkylpolyglucoside as well as 0.51g of hydroxyacetone under a hydrogen atmosphere of 1.1 bar pressure. Thereaction mixture was stirred and heated at 60° C. for 3 hours. Thus, thefinal concentration of hydrobromic acid was 0.025 mol/l, which equatesto a pH value of 1.6. The solution was extracted with ethyl acetate. Theextract was dried on anhydrous magnesium sulfate. The enantiomericexcess was then determined by chiral GC as in Example 1. As a result,the conversion was 91% and the purity of the (S)-form of 1,2-propanediolwas more than 97% ee.

Working Example 9

The catalyst solution obtained according to Preparation II, but with(S)-SYNPHOS as chiral ligand is placed into an autoclave in the presenceof, 25 ml of ethanol, 37.5 ml of degassed water, 165 μl of a 45 wt. %hydrobromic acid solution, 2 ml alkylpolyglucoside as well as 0,428 g ofhydroxyacetone under a hydrogen atmosphere of 1.1 bar pressure. Thus,the final concentration of hydrobromic acid was 0.022 mol/l, whichequates to a pH value of 1.65. The reaction mixture was stirred andheated at 80° C. for 6 hours. The solution was extracted with ethylacetate. The extract was dried on anhydrous magnesium sulfate. Theenantiomeric excess was then determined by chiral GC as in Example 1. Asa result, the conversion was 90% and the purity of the (S)-form of1,2-propanediol was more than 97% ee.

Working Example 10

The catalyst solution obtained according to Preparation III, but with(S)-SYNPHOS as chiral ligand is placed into an autoclave in the presenceof, 25 ml of ethanol, 37.5 ml of degassed water, 165 μl of a 45 wt. %hydrobromic acid solution, 2 ml alkylpolyglucoside as well as 0,428 g ofhydroxyacetone under a hydrogen atmosphere of 1.1 bar pressure. Thus,the final concentration of hydrobromic acid was 0.0236 mol/l, whichequates to a pH value of 1.63. The reaction mixture was stirred andheated at 80° C. for 6 hours. The solution was extracted with ethylacetate. The extract was dried on anhydrous magnesium sulfate. Theenantiomeric excess was then determined by chiral GC as in Example 1. Asa result, the conversion was 90% and the purity of the (S)-form of1,2-propanediol was more than 97% ee.

Working Example 11

The catalyst solution obtained according to Preparation III, but with(S)-SYNPHOS as chiral ligand was placed into an autoclave in thepresence of 30 ml of heptane, 20 ml of degassed water, 110 μl of a 45wt. % hydrobromic acid solution, 1 g alkylpolyglucoside as well as5.4*10⁻³ mol of hydroxyacetone under a hydrogen atmosphere of 4.7 barpressure. Thus, the final concentration of hydrobromic acid was 0.0455mol/l, which equates to a pH value of 1.34. The reaction mixture wasstirred and heated at 125° C. for 3 hours. The solution was extractedwith ethyl acetate. The extract was dried on anhydrous magnesiumsulfate. The enantiomeric excess was then determined by chiral GC as inExample 1. As a result, the conversion was 90% and the purity of the(S)-form of 1,2-propanediol was more than 97% ee.

Working Example 12

The catalyst solution obtained according to Preparation III, but with(R)-SYNPHOS as chiral ligand was placed into an autoclave in thepresence of 30 ml of heptane, 20 ml of degassed water, 110 μl of a 45wt. % hydrobromic acid solution, 1 g alkylpolyglucoside as well as5.4*10⁻³ mol of 2,4-pentanedione under a hydrogen atmosphere of 4.7 barpressure. Thus, the final concentration of hydrobromic acid was 0.0455mol/l, which equates to a pH value of 1.34. The reaction mixture wasstirred and heated at 125° C. for 6 hours. The solution was extractedwith ethyl acetate. The extract was dried on anhydrous magnesiumsulfate. The enantiomeric excess was then determined by chiral GC as inExample 1. As a result, the conversion was 90% and the purity of the(R,R)-form of 2,4-pentanediol was more than 99% ee.

The invention claimed is:
 1. A method for converting a precatalystcomplex to an active catalyst complex, wherein said precatalyst complexand said active catalyst complex comprise a ruthenium atom and anoptically active ligand that is insoluble in water, and wherein saidactive catalyst complex comprises a monohydride and a water molecule,said method comprising the steps of: a) providing an activation solventsystem comprising water, b) adding to, particularly solving in, saidactivation solvent system said precatalyst complex, a solubilizer, anacid, and hydrogen, characterized in that the pH value of saidactivation solvent system is equal or below 2 after addition of saidacid.
 2. The method according to claim 1, wherein said activationsolvent system comprises ≧50% (v/v), ≧75% (v/v), ≧80% (v/v), ≧90% (v/v),≧99% (v/v) or 100% water.
 3. The method according to claim 1, whereinsaid solubilizer is a surfactant that is capable of forming micelles inwater and that is resistant to hydrolysis at pH≦2.
 4. The methodaccording to claim 1, wherein said optically active ligand is selectedfrom the group consisting of:5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxane;(5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole;2,2′-bis(diphenylphosphino)-1,1′-binaphthyl;O-isopropyliden-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane;ethane-1,2-diylbis[(2-methoxyphenyl)phenylphosphane];(bis(diphenylphosphino)butane;(3-diphenylphosphanyl-2-bicyclo[2.2.1]hept-5-enyl)-diphenyl-phosphane;(1-benzyl-4-diphenylphosphanyl-pyrrolidin-3-yl)-diphenyl-phosphane;(2-diphenylphosphanyl-1-methyl-ethyl)-diphenyl-phosphane;[2-(diphenylphosphanylmethyl)cyclohexyl]methyl-diphenyl-phosphane;tert-butyl 4-benzhydryl-2-(2,2-diphenylethyl)pyrrolidine-1-carboxylate;[2-(1-naphthyl)phenyl]-[2-[2-(1-naphthyl)phenyl]phosphanylethyl]phosphane,[2-(2-diphenylphosphanyl-6-methoxy-phenyl)-3-methoxy-phenyl]-diphenyl-phosphane;[4-chloro-2-(3-chloro-6-diphenylphosphanyl-2-methoxy-phenyl)-3-methoxy-phenyl]-diphenyl-phosphane;[5-chloro-2-(4-chloro-2-diphenylphosphanyl-6-methoxy-phenyl)-3-methoxy-phenyl]-diphenyl-phosphane;[2-(6-diphenylphosphanyl-2,3,4-trimethyl-phenyl)-3,4,5-trimethyl-phenyl]-diphenyl-phosphane;[3-(4-diphenylphosphanyl-2,6-dimethoxy-3-pyridyl)-2,6-dimethoxy-4-pyridyl]-diphenyl-phosphane;[4-(4-diphenylphosphanyl-2,5-dimethyl-3-thienyl)-2,5-dimethyl-3-thienyl]-diphenyl-phosphane;[8-(7-diphenylphosphanyl-4-methyl-2,3-dihydro-1,4-benzoxazin-8-yl)-4-methyl-2,3-dihydro-1,4-benzoxazin-7-yl]-diphenyl-phosphane;and a compound characterized by formula III:

wherein n is 1, 2, 3, 4, 5 or 6.